Tissue Specific Insulin Receptor Knockout Models

In order to better understand whether severe insulin resistance can lead to frank diabetes, and to delineate the roles of the various insulin-sensitive tissues, the question has arisen whether it would be possible to induce diabetes in animal models harboring genetic defects leading to absence of insulin receptors in specific tissues (brain, muscle, liver, adipocytes, and pancreas islets). Therefore, animal models with "conditional knockouts of the insulin receptor" have been studied (Fig. 3). Although it had previously been widely thought that muscle insulin resistance would lead to diabetes, muscle-specific knockout models (9) did not develop diabetes, even if these animals did become obese. Similarly, neither adipocyte-specific (10) or brain-specific insulin receptor knockout animal models became diabetic (Fig. 2), although brain-specific animal models did become overweight, pointing to the physiological role of insulin as a (hypothalamic) satiety factor. However, liver-specific (11) and pancreas beta-cell-specific (12) knockout models did develop diabetes. The latter findings point to the great importance of insulin signaling within the beta cells for beta-cell growth and function.

However, the main positive conclusion of these studies is that even severe insulin resistance at the level of brain, muscle, or adipocyte does not lead to frank diabetes mellitus. The finding that severe insulin resistance in the liver or in the pancreas beta cells can lead to frank diabetes in itself cannot be taken as proof of the hypothesis that one or the other is an obligate part of the sequence of events of development of (human) type 2 diabetes.